Variation in tibial functionality and fracture susceptibility among healthy, young adults arises from the acquisition of biologically distinct sets of traits

Physiological systems like bone respond to many genetic and environmental factors by adjusting traits in a highly coordinated, compensatory manner to establish organ‐level function. To be mechanically functional, a bone should be sufficiently stiff and strong to support physiological loads. Factors impairing this process are expected to compromise strength and increase fracture risk. We tested the hypotheses that individuals with reduced stiffness relative to body size will show an increased risk of fracturing and that reduced strength arises from the acquisition of biologically distinct sets of traits (ie, different combinations of morphological and tissue‐level mechanical properties). We assessed tibial functionality retrospectively for 336 young adult women and men engaged in military training, and calculated robustness (total area/bone length), cortical area (Ct.Ar), and tissue‐mineral density (TMD). These three traits explained 69% to 72% of the variation in tibial stiffness ( p  < 0.0001). Having reduced stiffness relative to body size (body weight × bone length) was associated with odds ratios of 1.5 (95% confidence interval [CI], 0.5–4.3) and 7.0 (95% CI, 2.0–25.1) for women and men, respectively, for developing a stress fracture based on radiography and scintigraphy. K‐means cluster analysis was used to segregate men and women into subgroups based on robustness, Ct.Ar, and TMD adjusted for body size. Stiffness varied 37% to 42% among the clusters ( p  < 0.0001, ANOVA). For men, 78% of stress fracture cases segregated to three clusters ( p  < 0.03, chi‐square). Clusters showing reduced function exhibited either slender tibias with the expected Ct.Ar and TMD relative to body size and robustness (ie, well‐adapted bones) or robust tibias with reduced residuals for Ct.Ar or TMD relative to body size and robustness (ie, poorly adapted bones). Thus, we show there are multiple biomechanical and thus biological pathways leading to reduced function and increased fracture risk. Our results have important implications for developing personalized preventative diagnostics and treatments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98270/1/jbmr1879.pd

Functional polymorphisms in the P2X7 receptor gene are associated with stress fracture injury

Context: Military recruits and elite athletes are susceptible to stress fracture injuries. Genetic predisposition has been postulated to have a role in their development. The P2X7 receptor (P2X7R) gene, a key regulator of bone remodelling, is a genetic candidate that may contribute to stress fracture predisposition. Objective: To evaluate the putative contribution of P2X7R to stress fracture injury in two separate cohorts, military personnel and elite athletes. Methods: In 210 Israeli Defence Forces (IDF) military conscripts, stress fracture injury was diagnosed (n=43) based on symptoms and a positive bone scan. In a separate cohort of 518 elite athletes, self-reported medical imaging scan-certified stress fracture injuries were recorded (n=125). Non-stress fracture controls were identified from these cohorts who had a normal bone scan or no history or symptoms of stress fracture injury. Study participants were genotyped for functional SNPs within the P2X7R gene using proprietary fluorescence-based competitive allele-specific PCR assay. Pearson Chi-square (χ2) tests, corrected for multiple comparisons, were used to assess associations in genotype frequencies. Results: The variant allele of P2X7R SNP rs3751143 (Glu496Ala- loss of function) was associated with stress fracture injury, while the variant allele of rs1718119 (Ala348Thr- gain of function) was associated with a reduced occurrence of stress fracture injury in military conscripts (P<0.05). The association of the variant allele of rs3751143 with stress fractures was replicated in elite athletes (P<0.05), whereas the variant allele of rs1718119 was also associated with reduced multiple stress fracture cases in elite athletes (P<0.05). Conclusions: The association between independent P2X7R polymorphisms with stress fracture prevalence supports the role of a genetic predisposition in the development of stress fracture injury

Dietary intake and stress fractures among elite male combat recruits

<p>Abstract</p> <p>Background</p> <p>Appropriate and sufficient dietary intake is one of the main requirements for maintaining fitness and health. Inadequate energy intake may have a negative impact on physical performance which may result in injuries among physically active populations. The purpose of this research was to evaluate a possible relationship between dietary intake and stress fracture occurrence among combat recruits during basic training (BT).</p> <p>Methods</p> <p>Data was collected from 74 combat recruits (18.2 ± 0.6 yrs) in the Israeli Defense Forces. Data analyses included changes in anthropometric measures, dietary intake, blood iron and calcium levels. Measurements were taken on entry to 4-month BT and at the end of BT. The occurrence of stress reaction injury was followed prospectively during the entire 6-month training period.</p> <p>Results</p> <p>Twelve recruits were diagnosed with stress fracture in the tibia or femur (SF group). Sixty two recruits completed BT without stress fractures (NSF). Calcium and vitamin D intakes reported on induction day were lower in the SF group compared to the NSF group-38.9% for calcium (589 ± 92 and 964 ± 373 mg·d^-1, respectively, <it>p </it>< 0.001), and-25.1% for vitamin D (117.9 ± 34.3 and 157.4 ± 93.3 IU·d^-1, respectively, <it>p </it>< 0.001). During BT calcium and vitamin D intake continued to be at the same low values for the SF group but decreased for the NSF group and no significant differences were found between these two groups.</p> <p>Conclusions</p> <p>The development of stress fractures in young recruits during combat BT was associated with dietary deficiency before induction and during BT of mainly vitamin D and calcium. For the purpose of intervention, the fact that the main deficiency is before induction will need special consideration.</p

CANDIDATE GENE ANALYSIS IN ISRAELI SOLDIERS WITH STRESS FRACTURES

To investigate the association of polymorphisms within candidate genes which we hypothesized may contribute to stress fracture predisposition, a case-control, cross- sectional study design was employed. Genotyping 268 Single Nucleotide Polymorphisms- SNPs within 17 genes in 385 Israeli young male and female recruits (182 with and 203 without stress fractures). Twenty-five polymorphisms within 9 genes (NR3C1, ANKH, VDR, ROR2, CALCR, IL6, COL1A2, CBG, and LRP4) showed statistically significant differences (p < 0.05) in the distribution between stress fracture cases and non stress fracture controls. Seventeen genetic variants were associated with an increased stress fracture risk, and eight variants with a decreased stress fracture risk. None of the SNP associations remained significant after correcting for multiple comparisons (false discovery rate- FDR). Our findings suggest that genes may be involved in stress fracture pathogenesis. Specifically, the CALCR and the VDR genes are intriguing candidates. The putative involvement of these genes in stress fracture predisposition requires analysis of more cases and controls and sequencing the relevant genomic regions, in order to define the specific gene mutation

Musculoskeletal injuries in military personnel – descriptive epidemiology, risk factor identification, and prevention

Objectives: To provide an overall perspective on musculoskeletal injury (MSI) epidemiology, risk factors, and preventive strategies in military personnel. Design: Narrative review. Methods: The thematic session on MSIs in military personnel at the 5th International Congress on Soldiers’ Physical Performance (ICSPP) included eight presentations on the descriptive epidemiology, risk factor identification, and prevention of MSIs in military personnel. Additional topics presented were bone anabolism, machine learning analysis, and the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on MSIs. This narrative review focuses on the thematic session topics and includes identification of gaps in existing literature, as well as areas for future study. Results: MSIs cause significant morbidity among military personnel. Physical training and occupational tasks are leading causes of MSI limited duty days (LDDs) for the U.S. Army. Recent studies have shown that MSIs are associated with the use of NSAIDs. Bone MSIs are very common in training; new imaging technology such as high resolution peripheral quantitative computed tomography allows visualization of bone microarchitecture and has been used to assess new bone formation during military training. Physical activity monitoring and machine learning have important applications in monitoring and informing evidence-based solutions to prevent MSIs. Conclusions: Despite many years of research, MSIs continue to have a high incidence among military personnel. Areas for future research include quantifying exposure when determining MSI risk; understanding associations between health-related components of physical fitness and MSI occurrence; and application of innovative imaging, physical activity monitoring and data analysis techniques for MSI prevention and return to duty